The blood-brain barrier (BBB) blocks the passage of most macromolecules from the periphery into the brain and thus limits the uses of large molecule therapeutics where brain exposure is required. Transferrin receptor (TfR) is highly expressed at the BBB and can be used to transport such therapeutics across the BBB via a receptor-mediated transcytosis. Mouse models previously have been developed, in which the mouse TfR was replaced with a full-length human TfR cDNA, with the objective of evaluating the ability of potential therapeutics to cross the BBB. However, these transgenic mice were unhealthy and showed abnormally high TfR expression, low red blood cell count, and high serum iron concentration. Yu et al., Science Trans. Med., 6(261):261ra154 (2014). As a result, these existing mouse models are not suited for use as tools to evaluate therapeutics that are capable of crossing the BBB to treat brain diseases; models that are more representative of endogenous TfR expression and phenotype are required.